Phenylketonuria
May. 09, 2022
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This article includes discussion of globoid cell leukodystrophy, galactosylceramide lipidosis, and Krabbe disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive, rapidly progressive fatal disease when it occurs in infancy. The disease usually begins between the ages of 3 and 6 months with ambiguous symptoms, such as irritability or hypersensitivity to external stimuli, but soon progresses to severe mental and motor decline. Patients are initially hypertonic with hyperactive reflexes, but they later become flaccid and hypotonic. Blindness and deafness are common. Patients with late-onset forms, including adult onset, may present with blindness, spastic paraparesis, and dementia. Saposin A deficiency is a rare cause of Krabbe disease. Brain MRI has characteristic features that depend on the age of onset of the disease (infantile, juvenile, or adult). Optic nerve and cauda equina enlargement and enhancement is common, as well as midbrain atrophy. The presence of peripheral nerve enlargement detected by ultrasound strongly supports the diagnostic possibility of Krabbe disease (52). Newborn screening and presymptomatic hematopoietic stem cell transplantation have not yielded clear benefits.
• Globoid cell leukodystrophy may occur at any age, but the infantile type is the most common. | |
• Typical MRI changes that vary according to each phenotype suggest the diagnosis. | |
• The adult onset type is the most prevalent in certain populations such as Japan. | |
• Hematopoietic stem cell transplantation in presymptomatic infants only mitigates the disease and is not the optimal therapy it was once hoped to be. | |
• Measuring psychosine, a major offending metabolite in Krabbe disease, in dried blood spots helps in diagnosis and in differentiating infantile from later onset variants, as well as in monitoring disease progression and response to treatment. |
Globoid cell leukodystrophy, or Krabbe disease, was described in 1916. Krabbe reported the clinical and neuropathologic description of 5 cases that appeared to represent a new disease entity (49). Previous neuropathologic studies, however, had described the "diffuse gliosis" of brain that was later characterized as "diffuse brain-sclerosis" in Krabbe patients (11; 09). Collier and Greenfield in 1924 used the term "globoid cells" to describe the phagocytic cells that appeared unique to this disorder (20). Hallervorden suggested that these globoid cells may contain kerasin or cerebroside (34). Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (10; 05), and galactocerebroside was the only glycolipid that could produce globoid cells when injected into the central nervous system of experimental animals (03). Analytical biochemical studies of total brain lipids did not show an increase in galactosylcerebroside in this disease, but rather a lowering of total cerebroside and sulfatide and a reduced sulfatide-to-cerebroside ratio (86). Only a fraction of brain lipids enriched in the specialized globoid cells showed an increase in galactosylceramide (05). In 1970, Malone reported a deficiency of leukocyte galactosylceramide beta-galactosidase in a Krabbe disease patient (62); this was confirmed by Suzuki and Suzuki, who demonstrated the enzyme deficiency in the brain, liver, and spleen of 3 Krabbe disease patients (85). Psychosine, a related glycolipid, was suggested to be the toxic metabolite responsible for the pathogenesis of this disorder (65; 83). The gene for the galactosylceramidase (GALC) enzyme has been mapped to chromosome 14 (102), and the cDNA has been cloned by Chen and associates (16).
Initial clinical reports of Krabbe disease described the classic early infantile presentation (49). The early infantile presentation, which accounts for over 90% of globoid cell leukodystrophy, begins before 6 months of age in the majority of cases, and in 25% of cases, prior to 3 months of age (60; Wenger 1997). The disorder in these early-onset children has been classically categorized in 3 stages (33):
• Stage 1: Sensitivity to noise and light, periodic fever without infection, stagnation and then regression of development, and increased tone with normal deep tendon reflexes. | |
• Stage 2: Permanent opisthotonus, tonic flexion of arms and extension of legs, loss of nearly all previously acquired skills, myoclonic jerks, seizures, optic atrophy, and blindness. | |
• Stage 3: Immobile, decerebrate, hypotonic, and unable to feed. |
However, the disease progresses in a continuum as was demonstrated in a prospective study of a large cohort of children presenting at 0 to 5 months of age (08). Children may rarely present in the neonatal period, but this is an uncommon occurrence (60), and a prenatal onset was first suggested when a 5-month-old fetus was noted to have the characteristic neuropathologic findings (25). The cerebrospinal fluid protein is usually elevated (60).
Much less common is a late-infantile variant for which the age of onset is between 19 months and 4 years (57). The children have normal intelligence or are only moderately retarded during the first years, but then gradually develop ataxia, weakness, spasticity, and later dysarthria. Patients with onset after 12 months have less peripheral nerve involvement and slower disease progression (06). Visual loss with the early onset of optic atrophy, mental regression, occasional seizures, deafness, and normal peripheral nerves are the characteristic findings. A slowly progressive spinocerebellar degeneration associated with peripheral neuropathy, but without visual loss or dementia, has been reported (89). As in other forms of globoid cell leukodystrophy, cerebrospinal fluid protein is usually, but not always elevated (57). Peripheral neuropathy may be of the demyelinating type or predominantly axonal (61). These can very rarely have relatively high residual galactocerebrosidase activity (50).
Late-onset variants of globoid cell leukodystrophy have been somewhat arbitrarily defined as juvenile onset (beginning between 4 and 19 years of age), and adult onset (20 years of age and older) (Wenger 1997; 27; 55). These patients usually have optic nerve pallor, pes cavus, slowly progressive spastic tetraplegia, sensory-motor demyelinating neuropathy, hypodensity in the white matter in the parieto-occipital regions on cranial CT, and symmetric parieto-occipital predominant periventricular abnormality on brain MRI with high signal of the pyramidal tracts, eventually with involvement of the splenium of the corpus callosum and optic radiations, with preserved mental function in approximately one half of the affected individuals (77; 22). A detailed description of 20 patients with adult-onset Krabbe disease showed that the corticospinal tract was always affected, but other areas in the brain were also often involved, whereas the genu of the corpus callosum was always normal (21). The pyramidal tracts can be involved in isolation in middle age patients (90). The adult onset form is the most common phenotype in Japan (39). Cerebrospinal fluid protein is frequently not increased. The lifespan of individuals with the late-onset variant may vary, but survival for over 24 years has been reported (04). Interestingly, 82% of Chinese patients have late-onset Krabbe disease (101).
Untreated children with the early infantile form of globoid cell leukodystrophy rarely live past 2 years of age. The late-infantile variant may have a much more prolonged course, with death usually occurring 1 year to 6 years after onset. In 1 report, however, the patient was not diagnosed until 34 years of age despite symptoms beginning in the late infantile period (89). In juvenile-onset and adult-onset patients, the disease will frequently have a much more protracted course (55).
A 4-month-old child was evaluated because of a history of irritability that manifested as a high-pitched cry and poor feeding. The child was noted in the past to have unexplained fevers associated with episodes of extreme irritability. On examination the child was hypotonic and kept the hands continuously fisted. The deep tendon reflexes were reduced, but plantar stimulation caused an extensor response. No optic atrophy was appreciated. An EEG was only minimally abnormal with occasional paroxysmal beta noted over the vertex. CT scan demonstrated increased attenuation in the thalamus and basal ganglia, but decreased attenuation in the white matter. Studies included serum amino acids, urine organic acids, viral titers for congenital infections, serum lactate, and pyruvate, all of which were normal. Cerebrospinal fluid examination demonstrated normal cell count, lactate, and pyruvate, but protein was increased to 158 mg%. A leukocyte galactosylceramidase level was 0.03 nmol galactose/mg protein per hour with a control of 2.3 confirming the diagnosis of Krabbe disease. The child died of a respiratory infection at 15 months of age.
Globoid cell leukodystrophy is caused by a deficiency of the enzyme galactosylceramidase. The disease is inherited in an autosomal recessive manner.
Krabbe disease is categorized as a leukodystrophy because most of the neuropathologic changes are noted in the white matter of the brain and in the peripheral nerves. The typical neuropathologic findings in these patients include severe loss of oligodendroglia, myelin, and axons; dense astrocytic proliferation; and the presence of "globoid cells." In the murine model of Krabbe disease (a twitcher mouse), the oligodendrocyte loss is caused by an apoptotic depletion (87). Loss of myelin can also be seen in peripheral nerves; however, typical globoid cells are frequently not observed (63). Although the identification is somewhat controversial, these characteristic globoid cells appear to be specialized macrophages originating from mesoderm (03). Ultrastructurally, globoid cells may be mononuclear or multinuclear; the latter contain 2 types of membrane-bound tubules. These tubules are either slender twisted tubules similar to those observed in Gaucher disease or a larger straight or arched variety (98). Experimentally, the only glycolipid that could produce globoid cells when injected into the cerebral cortex was galactosylceramide (03). Initial biochemical studies of brains from patients with Krabbe disease demonstrated the accumulation of the glycolipid, galactosylceramide, only within a fraction of brain that was enriched in globoid cells (05). However, total glycolipid and sulfatide levels in white matter from these brains were reduced (05). The association between galactosylceramide and Krabbe disease was confirmed when the enzyme that degrades galactosylceramide, galactosylceramidase, was found to be deficient in the leukocytes, brain, liver, and spleen of Krabbe patients (62; 85). Data suggest that elevated expression of matrix metalloproteinase (MMP-3) and tenascin-C mediates the production of globoid cells in Krabbe disease (43; 19).
This enzyme, galactosylceramidase, hydrolyses not only galactosylceramide, but also other glycolipids containing a terminal beta-galactose group, such as lactosylceramide, monogalactosyl diglyceride, and galactosylsphingosine (psychosine) (65; 93; 92). In order to properly function, the galactosylceramidase enzyme requires a sphingolipid activator protein, saposin A or saposin C, which helps solubilize the protein-lipid complex (35). Saposin A and saposin C also activate the degradation of galactosylsphingosine (35). A very rare deficiency of saposin A leads to a clinical picture identical to that of early-infantile Krabbe disease caused by GALC enzyme deficiency (13). A second lysosomal enzyme, GM1 ganglioside beta-galactosidase, hydrolyzes GM1 ganglioside, and its deficiency is associated with the storage disease GM1 gangliosidosis. Different, but overlapping substrate specificity exists for these 2 beta-galactosidase enzymes; under certain conditions GM1 ganglioside beta-galactosidase can hydrolyze galactosylceramide, but not psychosine (48).
Although galactosylceramide does not accumulate in the white matter of affected individuals except in the specialized globoid cells (05), psychosine is increased in the brains of patients with Krabbe disease (83). Psychosine has been demonstrated to cause cell death and injury to oligodendrocytes in culture that can be ameliorated by the presence of compounds that activate protein kinase C, activate galactosylceramidase, or bind to psychosine (18). Researchers found that psychosine localizes to detergent resistant membrane microdomains (lipid rafts), perturbs natural and artificial membrane integrity, and inhibits protein kinase C translocation to the plasma membrane (36). These data strongly suggest that a significant component of psychosine toxicity is achieved through membrane perturbation rather than through protein-psychosine interactions (36). In the twitcher mouse, psychosine seems to accumulate in lipid rafts causing a maldistribution of cholesterol and specific proteins, which leads to a dysfunction of protein kinase C (94). Psychosine also inhibited fast axonal transport through the activation of axonal PP1 and GSK3beta in the axon (15). Abnormal levels of activated GSK3beta and abnormally phosphorylated kinesin light chains were found in nerve samples from a mouse model of Krabbe disease (15). It has been proposed that because of the overlapping substrate specificity of the beta-galactosidase enzymes, only psychosine and not galactosylceramide accumulates in the brains of Krabbe disease patients (83). It is this toxic psychosine or galactosylsphingosine accumulation that may be responsible for the apoptotic depletion of oligodendroglial cells and the abnormal myelination in this disease. Further confirmation of the role of psychosine in Krabbe disease has been obtained by deleting the activity of acid ceramidase in the Twitcher mouse (54). The combination of single gene defect prevented psychosine elevation in the Twitcher mouse and a marked improvement in its phenotype (54). This work also showed that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase. Although bone marrow transplantation normalizes the level of psychosine in the brain, transplanted mice still end up succumbing from the disease (59).
The gene for galactosylceramidase (GALC) was mapped to chromosome 14 (14q.31) by linkage analysis (102) and confirmed by in situ hybridization using a portion of the human cDNA for this gene (14). Following the difficult purification of the galactosylceramidase enzyme from human urine (17), the cDNA encoding GALC was cloned (16). Sodium dodecylsulfate-polyacrylamide gel electrophoresis of fractions containing the purified enzyme showed bands corresponding to 80 kD, between 50 and 52 kD, and 30 kD, all of which have a similar N-terminal amino acid sequence. This sequence similarity suggests that the 50 kD and 30 kD species are derived from the 80 kD precursor species (16; 17). The cDNA is 3.8 kb in length and contains a 2007 bp open reading frame that codes for 669 amino acids representing an unglycosylated protein with a molecular weight of 72,781 (17). This weight is consistent with the glycosylated 80 kD precursor form identified (16). Confirmation of the deduced amino acid sequence for the cDNA occurred following the purification of the enzyme from human leukocytes and the subsequent cloning using the polymerase chain reaction method (73). The entire gene structure and organization has been determined to consist of nearly 60 kb with 17 exons and 16 introns (58). The promoter region, located at the 149 to 112 nucleotide region from the initiation codon, contains 3 galactocerebroside-box-like sequences and 1 YY1 binding site (72). A common polymorphism in the human GALC gene occurs at nucleotide position 1637 in which either a T or C may be present. The enzyme derived from the 1637T allele has 1.5- to 2-fold more activity than the enzyme derived from 1637C, which explains the wide range of human GALC gene activity in the general population (23).
Molecular analyses demonstrated at least 73 mutations, including base transitions, polymorphisms, and deletions, that are associated with Krabbe disease, which can be seen at the Human Gene Mutation Database GALC web page. In infantile patients with Krabbe disease from Northern European ancestry, approximately 40% to 50% of cases have a mutant allele that has a 30 kb deletion beginning in intron 10 and extending past the 3’ end of the gene (46). In addition to the deletion on this allele, an invariable C to T transition at position 502 exists, which is a polymorphism seen in only about 4% of the population. Improved detection of mutations using comparative genomic hybridization (CGH) to analyze the GALC gene has been described (88). Most of the mutations causing infantile-onset disease are located on the region coding for the 30 kD subunit of the enzyme suggesting that this subunit is critical for the normal functioning of the enzyme (Wenger 1997). Adult-onset cases may also have the 502/del mutation on 1 allele, but many other mutations have been identified, which appear to occur predominantly in the region coding for the 50 kD subunit (28; 75; 23).
Globoid cell leukodystrophy that is inherited as an autosomal recessive disorder affects males and females equally and appears to be panethnic. The incidence of Krabbe disease in the general population is not known, but a report from Sweden suggested an incidence of 1.9 in 100,000 (33), whereas in Japan the calculated incidence was reported as 1 in 100,000 to 1 in 200,000 (84). The early infantile form of Krabbe disease is frequent in the Muslim Arab population in Israel, with a very high prevalence of approximately 1 out of 100 to 1 out of 150 live births (99).
In families previously identified through an affected child or by carrier detection, prenatal diagnosis is the only current method for prevention of globoid cell leukodystrophy.
It is often difficult to distinguish among children with the various forms of inherited degenerative diseases. Recognizing the pattern of abnormalities on brain MRI greatly facilitates the differentiation of Krabbe disease from other disorders (76). MRI imaging abnormalities in Krabbe disease vary according to the specific phenotype (01). Metachromatic leukodystrophy has many features similar to Krabbe disease, but the disease often begins in the second year of life and the CT and MRI scans are more likely to demonstrate white matter involvement, especially in the frontal regions (95). Canavan disease, a spongy degeneration of white matter, is associated with macrocephaly, hypotonia early in the course of the disease, and normal cerebrospinal fluid protein. Canavan disease has been associated with an accumulation of N-acetylaspartic acid in brain and urine and a deficiency of the enzyme aspartoacylase in fibroblasts (64). In Alexander disease, another cause of macrocephaly in infancy, CT images may show more evidence of low intensity in anterior white matter and contrast enhancement in caudate, fornices, and subependymal white matter (37). Another infantile leukodystrophy, Pelizaeus-Merzbacher disease, differs from Krabbe disease by the prominent nystagmus seen early in infancy and the slow development of spastic quadriplegia (100). GM2 gangliosidosis (Tay-Sachs disease) also begins in infancy, but it can be characterized by a cherry-red spot in the retina and the presence of early seizures. Other lysosomal storage diseases that begin in infancy, such as infantile Gaucher disease, Niemann-Pick disease, and Sandhoff disease, and the mucopolysaccharidoses can be distinguished from Krabbe disease by the presence of systemic signs (ie, organomegaly and dysostosis multiplex) (60).
The child suspected of having globoid cell leukodystrophy should have an MRI scan to evaluate the myelin development. Early in the course of the disease, when spasticity, fever, and irritability become apparent, the CT scan demonstrates increased density in the brainstem, thalami, caudate nuclei, corona radiata, cerebellar cortex, and periventricular and capsular white matter (74). MRI performed during these initial symptoms shows decreased T1 values and normal or slightly decreased T2 values in the abnormal areas demonstrated by CT scan, and large symmetric plaquelike areas on T1 and T2 values in the white matter of the centrum semiovale (74; 01). Optic nerve hypertrophy, thought to be due to extensive gliosis, has been noted on MRI studies in a child with early infantile-onset Krabbe disease (79). As the disease progresses, brain atrophy, decreased attenuation in white matter, and symmetric punctate high-density areas in corona radiata are noted on CT scan, whereas high attenuation on T2-weighted images and low attenuation on T1-weighted images are present in white matter on MRI scans (74; 01).
Remarkable brain MRI features include enlargement and, sometimes, enhancement of the optic nerves, chiasm, and, sometimes, other cranial nerves and cauda equina (30; 40), as well as selective involvement of the corticospinal tracts, which is often also present in the late-onset form (Krishnamoorthy et al 2010; 78). Rarely, brain MRI can be normal, even in the early-onset form (44). Subsequently, other studies performed in infantile-onset Krabbe disease have demonstrated a decreased signal on T2-weighted images from the thalamus and basal ganglia with increased T2-weighted signal in centrum semiovale, corpus callosum, internal capsule, midbrain, and pons. All parameters of diffusion-weighted imaging are abnormal, particularly radial diffusivity reflecting the white matter abnormality of Krabbe disease (68). Variable atrophy of the midbrain viewed sagittally may be rather useful and correlates with clinical severity and other neuroimaging aspects (103).
Cerebrospinal fluid in patients with early and late infantile forms of Krabbe disease show elevated protein (frequently 75 to 500 mg/dL) with normal cell counts (Wenger 1997). Cerebrospinal fluid glycolipids demonstrate reduced galactosylceramide and trace amounts of lactosylceramide, but no evidence of psychosine (45).
Electroencephalograms are usually normal during the early stages, but later the background slows and becomes irregular with frequent multifocal spike waves (42). Nerve conduction velocities are slowed in the early infantile form, an observation consistent with a demyelinating disorder (80), but may be normal in adult-onset patients. Electromyograms frequently show evidence of an axonal injury, with high amplitude, but a reduced number of motor units and occasional fibrillations (80). It should be emphasized that any of the known biomarkers, such as abnormal neuroimaging, brainstem evoked responses, and nerve conduction velocities and elevated CSF protein, may be normal in up to 25% of patients (24).
Ultrastructural data suggest that Krabbe disease may be diagnosed on the basis of electron microscopic inclusions seen in eccrine sweat glands (31). The inclusions appear to be similar to those seen in Schwann cells consisting of needle-like and cleft-type inclusions (31). The only specific test, however, that will definitely confirm the diagnosis of Krabbe disease is the measurement of galactosylceramidase activity in serum, leukocytes, or cultured fibroblasts. Although most patients have galactosylceramidase activity below 5% of mean normal levels, rare patients with high residual activity have been described (50). One consensus stresses the need to transplant patients in the early days of life and certainly in the first 30 days (53). Psychosine quantitation was found to be critical for the correct diagnosis of Krabbe disease in newborn screening (32). Measuring psychosine in dried blood spots helps to differentiate infantile from later onset Krabbe disease variants, as well as from GALC variant and pseudodeficiency carriers (32). Newborn screening for Krabbe disease in the state of New York yielded an incidence of infantile Krabbe disease of approximately 1 in 394,000, but it may be higher for later-onset forms (66). It has been increasingly applied, but the detection of mild or even non-disease-related variants is a confounder (67).
Symptomatic treatment is available for the severe irritability with either benzodiazepam or low-dose morphine (82).
Bone marrow transplantation has been used in a murine model of Krabbe disease, the twitcher mouse. The lifespan of the twitcher mouse was prolonged, with remyelination noted in peripheral nerves (97). Donor-derived macrophages could be demonstrated with extensive remyelination in the central nervous system of mice receiving bone marrow transplantation, and significant increases in galactocerebroside beta-galactosidase levels were noted along with reduction of galactosylceramide and psychosine in several organs (41; 38).
Bone marrow transplantation has been performed in several patients with some success. In a study of 5 patients with Krabbe disease (4 juvenile and 1 infantile onset) who received hematopoietic stem cell transplantation, all of the treated patients had significant improvements in their neurologic symptoms (51). The 4 late onset cases demonstrated improvement in MRI findings and reversal of protein elevation in the cerebrospinal fluid. Hematopoietic stem cell transplantation in infants prior to disease onset using umbilical cord blood leads to 100% survival, clear mitigation of cognitive decline, and, to a certain extent, a less severe motor phenotype (26). Although there is improvement in nerve conduction in the transplanted patients (81), they remain with substantial motor deficit. In the newborn screening performed in New York State in the past 8 years, 5 infants were diagnosed with early infantile Krabbe disease (91). Three died, 2 from transplantation-related complications and 1 from untreated disease. Two children who received hematopoietic transplantation have moderate to severe developmental delays. Bone marrow transplantation can also be useful for late-onset Krabbe disease (56). Newborn screening and transplantation in the following days after birth remains controversial. A group from Duke University suggests that transplantations before 30 days of age provide a significantly better mobility outcome, with 90% able to walk independently or with an assisted device, and 80% had normal speech (02). However, 60% required special resources in school (02). However, a New York state experience was much less positive (91). Assessment of the effect of hematopoietic stem cell transplantation can be done with the brain MRI Loe score (69). In a study of 18 patients, 15 patients were identified prenatally because of family history, and only 3 infants were identified by state-mandated newborn screening (96). From the results above, one can see that hematopoietic stem cell transplantation only delayed disease progression and was not an effective cure. Most patients treated early probably had prenatal-onset substantial motor impairments with spasticity because of corticospinal tract pathology. In addition, many survivors, particularly if transplanted after 30 days of age, had variable degrees of feeding, vision, hearing, language, and cognitive impairment.
Gene therapy using adeno-associated virus has been used in the animal model (70). Early intervention of combined hematopoietic stem cell transplantation and lentiviral-mediated gene transfer to newborn twitcher pups before postnatal day 2 prolonged survival, but it did not prevent ultimate axonal degeneration (29). A combination of more than one form of therapy might be needed (71). In a dog model of the disease, a combination of intravenous and intracerebroventricular injections of AAVrh10 targeted both the peripheral and the central nervous system (12). This approach showed a clear dose response and resulted in delayed onset of clinical signs, extended lifespan, correction of biochemical defects, and attenuation of neuropathology.
In experienced hands, general anesthesia is well tolerated in most children. Of the most commonly used procedures, central catheter placement/removal exhibited the highest complication rate (07).
The disease appears to begin in utero as globoid cells and galactosylsphingosine accumulation have been reported in the fetus (25; 47). Prenatal diagnosis is available using direct chorionic villus sampling at 8 weeks to 9 weeks, or later in pregnancy using cultured amniotic fluid cells (Wenger 1997).
No information was provided by the author.
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.
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